CN105777655B - Nabumetone replaces the alpha-crystal form and preparation method and the pharmaceutical composition containing it of Buddhist nun's tosilate - Google Patents
Nabumetone replaces the alpha-crystal form and preparation method and the pharmaceutical composition containing it of Buddhist nun's tosilate Download PDFInfo
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- CN105777655B CN105777655B CN201410822395.3A CN201410822395A CN105777655B CN 105777655 B CN105777655 B CN 105777655B CN 201410822395 A CN201410822395 A CN 201410822395A CN 105777655 B CN105777655 B CN 105777655B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
- C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The present invention provides compound N [the polymorphic α of 4 [(fluorophenyl of 3 chlorine 4) amino] 7 [3 (ethyoxyl) 6 quinazolyl] 4 (dimethylamino) 2 crotonamide tosilate, 1.5 crystalline hydrates, it has stable form and the fusing point determined, chemical stability is good, high temperature resistant and illumination, suitable for pharmaceutical applications.
Description
Technical field
The invention belongs to pharmaceutical technology field, specifically, is related to Nabumetone for Buddhist nun's tosilate crystalline hydrate
Novel crystal forms.
Background technology
The compound N of formula (1)-[4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- [3- (ethyoxyl) -6- quinazolyls] -4-
(dimethylamino) -2- crotonamides (Nabumetone replaces Buddhist nun) tosilate crystalline hydrate is suitable for treatment mammal
Excess proliferative disease, such as cancer.
The compound be the inhibitor of EGFR-TK such as EGF-R ELISA and can be used to treat or prevent with
The relevant disease of EGFR-TK such as EGF-R ELISA, such as cancer, particularly non-small cell lung cancer, colorectum
Cancer, refractory non small cell lung cancer, oophoroma, cancer of pancreas, breast cancer, glioma, brain tumor or neck cancer.
The content of the invention
It is an object of the present invention to provide N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- [3- (ethyoxyl) -6- quinoline azoles
Quinoline base] -4- (dimethylamino) -2- crotonamides (Nabumetone replaces Buddhist nun) tosilate crystalline hydrate a kind of novel crystal forms,
Its crystallize feature by fusing point, X-ray powder diffraction (XRD), differential scanning calorimetric analysis (DSC), thermogravimetric analysis (TG),
Infrared spectrum (IR), elementary analysis are characterized, and the crystal formation possesses the performance prepared required for solid pharmaceutical preparation.
Second object of the present invention is to provide N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- [3- (ethyoxyl) -6- quinolines
Oxazoline base] -4- (dimethylamino) -2- crotonamides (Nabumetone replaces Buddhist nun) tosilate crystalline hydrate novel crystal forms preparation
Method.
It is also another object of the present invention to provide contain the N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- [3- (ethoxies
Base) -6- quinazolyls] -4- (dimethylamino) -2- crotonamides (Nabumetone replaces Buddhist nun) tosilate crystalline hydrate is newly brilliant
The pharmaceutical composition of type.
The present inventor is preparing the N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- [3- (ethyoxyl) -6- quinazolines
Base] during -4- (dimethylamino) -2- crotonamides (Nabumetone replaces Buddhist nun) tosilate crystalline hydrate, pass through weight
The method of crystallization crystallizes to the material crude product, obtains the novel crystal forms of 1.5 crystallizations water, i.e. alpha-crystal form.By to this crystallize into
The measurement of row fusing point, X-ray powder diffraction, DSC, TG, IR, elementary analysis etc. detect and analysis, and the crystallization for confirming acquisition is a kind of
New crystallization, referred to as N- [4- [(the chloro- 4- fluorophenyls of 3-) ammonia] -7- [3- (ethyoxyl) -6- quinazolyls] -4- (dimethylaminos
Base) -2- crotonamides 1.5 crystallizations water of tosilate alpha-crystal form.
According to an aspect of the present invention, N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- [3- (ethyoxyl) -6- quinazolines
Base] -4- (dimethylamino) -2- crotonamides (Nabumetone replaces Buddhist nun) 1.5 crystalline hydrates of tosilate alpha-crystal form, when
When carrying out X-ray powder diffraction with Cu radiation sources, described alpha-crystal form be included in positioned at 2 θ be 5.0 ± 0.2,17.6 ± 0.2,
The characteristic diffraction peak of 18.7 ± 0.2 (°), the relative intensity (I/I at these peaks0) be all higher than or equal to 20%.Further, institute
State crystallization in X-ray powder diffraction can also further include positioned at 2 θ be 12.1 ± 0.2,14.5 ± 0.2,15.6 ±
0.2nd, the characteristic diffraction peak of 20.1 ± 0.2,22.0 ± 0.2,25.4 ± 0.2,26.0 ± 0.2 and 26.3 ± 0.2 (°), these peaks
Relative intensity be all higher than or equal to 7% (see Fig. 1).
Wherein " ± 0.2 " the measurement error scope to allow.
The alpha-crystal form of the present invention can be characterized by X-ray powder diffraction collection.It is characterized in that its x-ray powder
Diffracting spectrum has the characteristic peaks of above-mentioned 2 θ ° of expression, and its relative intensity is close to following numerical value：
Term " close " herein refers to the uncertainty of relative intensity measure value.It is skilled artisan understands that relatively strong
The uncertainty of degree is highly dependent on measuring condition.The uncertainty of relative intensity is highly dependent on measuring condition.Relative intensity
Value can change or preferably change in the range of ± 10% for example in the range of ± 25%.
Above-mentioned alpha-crystal form has the X-ray powder diffraction pattern shown in Fig. 1.
The present invention is using means of differential scanning calorimetry (DSC) technology to N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- [3- (second
Epoxide) -6- quinazolyls] -4- (dimethylamino) -2- crotonamides (Nabumetone replaces Buddhist nun) 1.5 crystallizations water of tosilate
The alpha-crystal form of compound is characterized (see Fig. 2), wherein the Endotherm Maximum with means of differential scanning calorimetry is at 133 DEG C.The endothermic process
An endothermic peak is shown as on DSC spectrograms；
The present invention is using Thermogravimetric analysis to N- [4- [(the chloro- 4- fluorophenyls of 3-) ammonia] -7- [3- (ethyoxyl) -6- quinoline azoles
Quinoline base] alpha-crystal form of -4- (dimethylamino) -2- crotonamides (Nabumetone replaces Buddhist nun) 1.5 crystalline hydrates of tosilate enters
Row is characterized (see Fig. 3), wherein being characterized in that thermogravimetric spectrogram (TG) is shown in 169 DEG C of weightlessness 2.5%, illustrates there is knot at this temperature
Brilliant water loses.
The infared spectrum of the alpha-crystal form of 1.5 crystalline hydrates of the present invention as shown in figure 4, wherein 3419,3284,
3052、2930、2732、2589、1695、1640、1575、1543、1524、1498、1452、1400、1368、1328、1266、
1238、1218、1185、1160、1121、1033、1008、814、684、568、500cm-1Have compared with strong absworption peak.
The Elemental analysis data of the alpha-crystal form of the present invention (is differed within ± 0.3%) with theoretical calculation, and further confirmation should
Compound contains 1.5 crystallizations water (see the table below).
According to another aspect of the present invention, prepare above-mentioned N- [4- [(the chloro- 4- fluorophenyls of 3-) ammonia] -7- [3- (ethyoxyl) -
6- quinazolyls] -4- (dimethylamino) -2- crotonamides (Nabumetone replaces Buddhist nun) 1.5 crystalline hydrates of tosilate α
The method of crystal formation includes：By N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- [3- (ethyoxyl) -6- quinazolyls] -4- (diformazans
Base amino) -2- crotonamides (Nabumetone replaces Buddhist nun) tosilate crude product, it is added to C1-C4The in the mixed solvent of alkyl alcohol and water
Or it is added to C3-C4The in the mixed solvent of alkyl ketone and water, it is heated to reflux to dissolving；Start to cool after solution clarification, it is solid to separating out
Body, solid is collected by filtration, the solid of collection is dried under reduced pressure and produces alpha-crystal form.Described alcohol is selected from methanol, ethanol, propyl alcohol, isopropyl
Alcohol and butanol, preferably ethanol；The volume ratio of alcohol and water (V/V) 11:1~20:1；Described ketone is selected from acetone, methyl ethyl ketone
With positive butanone etc., preferably acetone, the volume ratio (V/V) of ketone and water is 11:1~20:1；Described crude product and the proportioning of solvent
It is 1 (g) for w/v (W/V)：5~30 (ml), preferably 1:12(g/ml).Solution is preferably heated to 50~80 DEG C,
More preferably alcohol and water mixed solvent is heated to 70 DEG C, and ketone and water mixed solvent are heated to 60 DEG C.According to this embodiment, analysis is entered admittedly
Row 2~8 hours, more preferably 4 hours.It is 0~40 DEG C, preferably 5~15 DEG C to analyse solid temperature degree.The solid completely rear filtering of analysis, drying temperature
Spend for 30~60 DEG C, preferably 45 DEG C.
According to another aspect of the invention, there is provided contain N- of the present invention [4- [(the chloro- 4- fluorophenyls of 3-) ammonia] -7- [3- (second
Epoxide) -6- quinazolyls] -4- (dimethylamino) -2- crotonamides (Nabumetone replaces Buddhist nun) 1.5 crystallizations water of tosilate
The pharmaceutical composition of the alpha-crystal form of compound.Said composition contains the crystal compound and optional pharmaceutically acceptable load
Body and/or excipient.
Aforementioned pharmaceutical compositions can be configured to be available for the form of administration further according to conventional formulation method, including it is oral or
Parenteral administration forms.Be available for administration form in, should include therapeutically effective amount N- [4- [(the chloro- 4- fluorophenyls of 3-) ammonia]-
The α of 7- [3- (ethyoxyl) -6- quinazolyls] -4- (dimethylamino) -2- crotonamides (Nabumetone replaces Buddhist nun) tosilate
Crystal formation.It is so-called that " therapeutically effective amount " refers at this dose, compound of the invention can improve or mitigate disease symptomses, or energy
It is enough to suppress or block advancing of disease.
Rule of thumb and consider the standard method and bibliography of this area, those skilled in the art can easily select
Select various carriers and/or excipient and determine its dosage.
N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- [3- (ethyoxyl) -6- quinazolyls] -4- (dimethyl of the present invention
Amino) application and Nabumetone of -2- crotonamides (Nabumetone replaces Buddhist nun) tosilate alpha-crystal form replace Buddhist nun's tosilate one
Cause, for treating excess proliferative disease, preferably described excess proliferative disease is cancer, including but not limited to non-small cell
Lung cancer, colorectal cancer, refractory non small cell lung cancer, cancer of pancreas, oophoroma, breast cancer, glioma, the cancer of the brain or neck
Cancer.
The present invention be prepared N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- [3- (ethyoxyl) -6- quinazolyls] -
The alpha-crystal form of 4- (dimethylamino) -2- crotonamides (Nabumetone replaces Buddhist nun) tosilate, it has stable form and determination
Fusing point, chemical stability is good, high temperature resistant and illumination, N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- [3- of this novel crystal forms
(ethyoxyl) -6- quinazolyls] -4- (dimethylamino) -2- crotonamides (Nabumetone replaces Buddhist nun) tosilate possesses system
Performance required for standby solid pharmaceutical preparation, and store conveniently, production operation is more easy, and quality is more easy to control.
Brief description of the drawings
Fig. 1 is the polymorphic α of the gained of the embodiment of the present invention 1 X ray diffracting spectrum；
Fig. 2 is the polymorphic α of the gained of the embodiment of the present invention 1 DSC collection of illustrative plates；
Fig. 3 is the polymorphic α of the gained of the embodiment of the present invention 1 TG collection of illustrative plates；
Fig. 4 is the polymorphic α of the gained of the embodiment of the present invention 1 IR collection of illustrative plates；
Fig. 5 is the polymorphic α of the gained of the embodiment of the present invention 1 HPLC collection of illustrative plates.
Embodiment
All raw materials and reagent are commercially available.
It is prepared by crude product：
N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- [3- (ethyoxyl) -6- quinazolyls] -4- (dimethylamino) -
2- crotonamides (Nabumetone replaces Buddhist nun) are using N- (the chloro- 4- fluorophenyls of 3-) fluoro- 6- nitros -4- quinazolines amine of -7- as initiation material, reference
Prepared by method similar patent WO2007085638, salification process referenced patent WO2012121764 preparation method.
Prepare N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- [3- (ethyoxyl) -6- quinazolyls] -4- (dimethylaminos
Base) -2- crotonamides (Nabumetone replaces Buddhist nun) tosilate alpha-crystal form
[embodiment 1]
Take 200g Nabumetones to be added to for Buddhist nun's tosilate crude product in reaction bulb, add 2400ml acetone and mixing for water
(V/V=12 in bonding solvent:1) lower temperature rising reflux, is stirred to 60 DEG C.10min is stirred after dissolving, then is cooled to 5~15 DEG C, to admittedly
Body is separated out and is stirred for crystallization 4h, filters, and filter cake is eluted with acetone.Filter cake is helped dry in 45 DEG C of forced air dryings with phosphorus pentoxide.
Off-white powder 163g, yield 81.5%.It is 3.3% with karl Fischer analyzer detection moisture.Obtained compound is 1.5
N- [4- [(the chloro- 4- fluorophenyls of 3-) ammonia] -7- [3- (ethyoxyl) -6- quinazolyls] -4- (dimethylamino) -2- of the crystallization water
Crotonamide tosilate crystal formation α.
Compound Characters Identification is as shown in Fig. 1~Fig. 5.
The test condition of embodiment sample：
(1) XRD：
Detecting instrument：Sharp shadow (Empyrean) X-ray diffractometer
Testing conditions：Cu target K alpha rays, voltage 40kV, electric current 40mA, 1/32 ° of divergent slit, 1/16 ° of antiscatter slits,
Antiscatter slits 7.5mm, 2 θ scopes：3 ° -50 °, 0.02 ° of step-length, often walk residence time 40S.
Detect foundation：The ray powder diffraction method testing results of the People's Republic of China (PRC) (version two in 2010) Ⅸ F of annex Ⅹ：
Such as Fig. 1.
(2) DSC：
Detecting instrument：German NETZSCH companies DSC 204F1 differential scanning calorimeters
Testing conditions：Atmosphere：N2 (purity：>=99.99%), 20ml/min
Scanning imaging system：180 DEG C are warming up to from room temperature with 10 DEG C/min, records heating curve.
Detect sample quality：Sample 1：2.27mg (uses aluminum sample disc)
Detect foundation：JY/T 014-1996 heat analysis method general rules
Testing result：Such as Fig. 2.
(3) TG：
Detecting instrument：German NETZSCH company's Ts G209 thermogravimetric analyzers
Testing conditions：Atmosphere：Air, 20ml/min
Scanning imaging system：Room temperature~700 DEG C, heating rate：10℃/min.
Detect foundation：JY/T 014-1996 heat analysis method general rules
Testing result：Such as Fig. 3.
(4) infrared spectrum：
Detecting instrument：FT-IR NICOLET6700 (Germany)
Testing conditions：Pellet technique
Detect foundation：GB/T 6040-2002 infrared spectrum analysis general rules
Testing result：Such as Fig. 4.
(5) HPLC
Detecting instrument：The series of Agilent 1260 (U.S.)
Testing conditions：
Chromatographic column：Waters C18
Mobile phase A：Acetonitrile-Mobile phase B (70:30)
Mobile phase B：0.05mol/l ammonium dihydrogen phosphates (pH=7.3)
Column temperature：30 DEG C of Detection wavelengths：247nm.
Detect foundation：《Chinese Pharmacopoeia》Two annex VD high performance liquid chromatographies
Testing result：Such as Fig. 5
[embodiment 2]
Take 200g Nabumetones to be added to for Buddhist nun's tosilate crude product in reaction bulb, add 1600ml acetone and mixing for water
(V/V=10 in bonding solvent:1) lower temperature rising reflux, is stirred to 60 DEG C.10min is stirred after dissolving, then is cooled to 5~15 DEG C, to admittedly
Body is separated out and is stirred for crystallization 4h, filters, and filter cake is eluted with acetone.Filter cake is helped dry in 45 DEG C of forced air dryings with phosphorus pentoxide.
Off-white powder 154g, yield 77.0%.It is 4.4% with karl Fischer analyzer detection moisture.Obtained compound is 2 knots
N- [4- [(the chloro- 4- fluorophenyls of 3-) ammonia] -7- [3- (ethyoxyl) -6- quinazolyls] -4- (dimethylamino) -2- fourths of brilliant water
Acrylamide tosilate crystal formation β.
[other embodiment]
20g Nabumetones are respectively taken to be added to for Buddhist nun's tosilate crude product in reaction bulb, the experiment behaviour of reference implementation example 1~2
Carry out following test：
N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- [3- (ethyoxyl) -6- quinazolyls] -4- (dimethylamino) -
The study on the stability of 2- crotonamides (Nabumetone replaces Buddhist nun) tosilate crystal formation
[embodiment 3]
The crystal formation α and β of acquisition are subjected to study on the stability (accelerated tests of 10 days), 40 DEG C, 60 DEG C, humidity 75%,
92.5%th, the moisture of novel crystal forms, purity, maximum single miscellaneous and total miscellaneous data with 0 day are contrasted under illumination condition, as a result shown
Show the stable crystal form of acquisition.And free alkali (N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- [3- (ethyoxyl) -6- quinazolines
Base] -4- (dimethylamino) -2- crotonamides) under the conditions of 60 DEG C, degraded is obvious, illustrates stability of the high temperature to free alkali
Have an impact.
The crystal formation α influence factor result of the tests of table 1
The crystal formation β influence factor result of the tests of table 2
The free alkali influence factor result of the test of table 3
The preparation method of free alkali：Free alkali using N- (the chloro- 4- fluorophenyls of 3-) the fluoro- 6- nitros -4- quinazolines amine of -7- as rise
It is prepared by beginning raw material, similar referenced patent WO2007085638 method.
The preparation of solid pharmaceutical preparation
【Embodiment 4】The preparation of solid pharmaceutical preparation
Prescription 1：
Preparation method：Mentioned component is mixed according to conventional formulation method, direct tablet compressing.
Prescription 2：
Preparation method：Nabumetone is for 1.5 crystalline hydrate alpha-crystal forms of Buddhist nun's tosilate and mannitol, lactose, PVPP
It is well mixed by equivalent multiplication method, adds the HPMC solution prepared in advance and softwood, the granulation of 20 mesh sieves, 60 DEG C of 30 points of dryings are made
Clock, 18 mesh sieve whole grains, superfine silica gel powder is added, be well mixed, load 2#Capsule.
Prescription 3：
Preparation method：Mentioned component is mixed according to conventional formulation method, direct tablet compressing.
【Embodiment 5】Influence factor check experiment
3 batches of samples are prepared by the technique of prescription 1~3 in embodiment 4, after elementary item investigation is qualified, carry out light respectively
According to high temperature and high wet test, investigating appearance character, content and the dissolution rate of sample.The result of influence factor shows that sample is in height
Property is stable under gentle illumination condition, can refer to prescription and technique as preparation, but prescription 3 is 25 DEG C, RH75% and 25
DEG C, the easy moisture absorption under the conditions of RH92.5%, easily produce catabolite under light illumination.
Table 4
| Inspection target | Prescription 1 | Prescription 2 | Prescription 3 |
| Dissolution rate | It is good | It is good | Difference |
| Compressibility | It is good | / | Preferably |
| Disintegration | It is good | Preferably | Difference |
The purpose for developing crystal formation mainly solves the problems, such as dissolution rate, increases dissolution.Tried according to 2010 editions USP dissolutions
Test show prescription 1~2 its in 15 minutes dissolution rates more than 80%.And prescription 3 only had less than 70% in 15 minutes dissolution rates.
On the premise of auxiliary material is consistent, every inspection target of prescription 1 is better than prescription 3, therefore the product of alpha-crystal form and free alkali not only exists
Fusing point, solubility, Crystal solubility etc. are variant, and the stability of the latter, preparation dissolution rate, compressibility, disintegration etc. are each
Item inspection target is all not as the Nabumetone of the present invention replaces 1.5 crystalline hydrate alpha-crystal forms of Buddhist nun's tosilate.
The description to better embodiment of the present invention is not intended to limit the present invention above, and those skilled in the art can be according to this
Various changes or deformation are made in invention, without departing from the spirit of the present invention, all should belong to the models of appended claims of the present invention
Enclose.
Claims (8)
- Formula 1. (1) compound N-[4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- ethoxyquin oxazoline -6- bases] -4- (dimethylaminos Base) -2- crotonamide tosilate alpha-crystal form, the alpha-crystal form is N- [4- [(the chloro- 4- fluorine of 3- containing 1.5 crystallizations water Phenyl) amino] -7- ethoxyquin oxazoline -6- bases] -4- (dimethylamino) -2- crotonamide p-methyl benzenesulfonic acid salt hydrates, It has 2 θ ° be 5.0 ± 0.2,12.1 ± 0.2,14.5 ± 0.2,15.6 ± 0.2,17.6 ± 0.2,18.7 ± 0.2,20.1 ± 0.2nd, the X-ray powder diffraction pattern of 22.0 ± 0.2,25.4 ± 0.2,26.0 ± 0.2 and 26.3 ± 0.2 characteristic peaks represented
- 2. N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- ethoxyquin oxazoline -6- bases] -4- according to claim 1 The alpha-crystal form of (dimethylamino) -2- crotonamide tosilate, it is characterised in that described 2 θ ° of relative intensity I/I0 About following numerical value：
- 3. N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- ethoxyquin oxazolines -6- according to claim any one of 1-2 Base] -4- (dimethylamino) -2- crotonamide tosilate alpha-crystal form, it is characterised in that the DSC of the alpha-crystal form is swept The maximum endothermic transition retouched is about at 133 DEG C.
- 4. N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- ethoxyquin oxazolines -6- according to claim any one of 1-2 Base] -4- (dimethylamino) -2- crotonamide tosilate alpha-crystal form, it is characterised in that thermogravimetric spectrogram is shown in 169 DEG C weightlessness 2.5%.
- 5. N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- ethoxyquin oxazolines -6- according to claim any one of 1-2 Base] -4- (dimethylamino) -2- crotonamide tosilate alpha-crystal form, it is characterised in that measured with KBr tablettings red Outer absorption collection of illustrative plates, it is about 3419,3284,3052,2930,2732,2589,1695,1640,1575,1543,1524,1498, 1452、1400、1368、1328、1266、1238、1218、1185、1160、1121、1033、1008、814、684、568、 500cm-1There is absworption peak at place.
- 6. prepare N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- ethoxyquin oxazoline -6- bases] -4- described in claim 1 The method of the alpha-crystal form of (dimethylamino) -2- crotonamide tosilate, comprises the steps：1) by N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- ethoxyquin oxazoline -6- bases] -4- (dimethylamino) -2- butylene Acid amides tosilate crude product, is added to C1-C4The in the mixed solvent of alkyl alcohol and water is added to C3-C4Alkyl ketone and water In the mixed solvent, be heated to reflux to dissolving；Wherein described alkylol is selected from methanol, ethanol, propyl alcohol, isopropanol and butanol, and the volume ratio of alcohol and water is 11:1~20: 1；Described alkyl ketone is selected from acetone, methyl ethyl ketone and positive butanone, and the volume ratio of ketone and water is 11:1~20:1；Based on g/ml, the proportioning of described crude product and solvent is w/v 1：5~30, heating-up temperature is 50~80 DEG C；2) start to cool after solution clarification, to solid is separated out, solid is collected by filtration, the solid of collection is dried under reduced pressure and produces α crystalline substances Type；Wherein analyse and carry out 2~8 hours admittedly, it is 0~40 DEG C to analyse solid temperature degree, and analysis is admittedly completely rear to filter, and drying temperature is 30~60 DEG C.
- 7. the preparation method described in claim 6, the alkylol wherein described in step 1) is ethanol, and alkyl ketone is acetone, is pressed G/ml is counted, and the w/v of crude product and solvent is 1:12, alcohol and water mixed solvent is heated to 70 DEG C, and ketone and water mixed solvent add Heat is to 60 DEG C；The analysis solid time is 4 hours in step 2), and analysis solid temperature degree is 5~15 DEG C, and drying temperature is 45 DEG C.
- 8. contain N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- ethoxyquin oxazoline -6- bases] -4- described in claim 1 The pharmaceutical composition of the alpha-crystal form of (dimethylamino) -2- crotonamide tosilate.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410822395.3A CN105777655B (en) | 2014-12-25 | 2014-12-25 | Nabumetone replaces the alpha-crystal form and preparation method and the pharmaceutical composition containing it of Buddhist nun's tosilate |
| US15/539,070 US9957237B2 (en) | 2014-12-25 | 2015-12-22 | Crystal form of neptinib di-p-methylbenzenesulfonate, preparation method thereof, and pharmaceutical composition containing same |
| PCT/CN2015/098239 WO2016101867A1 (en) | 2014-12-25 | 2015-12-22 | Α-crystal form of naproxen imatinib p-toluene sulfonate, preparation method thereof, and pharmaceutical composition containing same |
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| CN107759570B (en) * | 2016-08-18 | 2019-09-03 | 山东诚创医药技术开发有限公司 | A kind of refining methd of his tosilate of department, Top |
| CN106389435B (en) * | 2016-09-05 | 2019-07-05 | 深圳海王医药科技研究院有限公司 | It is a kind of to replace Buddhist nun or the pharmaceutical composition and its impurity control method of its salt containing Nabumetone |
| CN106908531B (en) * | 2017-02-22 | 2019-08-06 | 深圳海王医药科技研究院有限公司 | A kind of Gradient High Performance Liquid Chromatography measures Nabumetone simultaneously for Buddhist nun's Photodegradation Products and other methods in relation to substance |
| CN114644642B (en) * | 2022-04-06 | 2023-05-12 | 深圳海王医药科技研究院有限公司 | Crystal form A of thienopyridine compound, preparation method and pharmaceutical composition thereof |
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| WO2016101867A1 (en) | 2016-06-30 |
| CN105777655A (en) | 2016-07-20 |
| US20170342037A1 (en) | 2017-11-30 |
| US9957237B2 (en) | 2018-05-01 |
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